Bifunctional Schiff base/Ti(IV) catalysts for enantioselective cyanoformylation of aldehydes with ethyl cyanoformate

Article abstract of DOI:10.1002/aoc.2951

A new bifunctional titanium/Schiff base catalyst was developed for the enantioselective cyanoformylation of aldehydes with ethyl cyanoformate. The reaction proceeded smoothly with a mild reaction condition to afford the cyanohydrin ethyl carbonates in hig

Full text of DOI:10.1002/aoc.2951

Full Paper
Received: 15 September 2012
Revised: 7 November 2012
Accepted: 8 November 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2951
Bifunctional Schiff base/Ti(IV) catalysts for
enantioselective cyanoformylation of aldehydes
with ethyl cyanoformate
Nan Jia, Lin Yaoa, Wei Hea* and Yurong Lib*
A new bifunctional titanium/Schiff base catalyst was developed for the enantioselective cyanoformylation of aldehydes with ethyl
cyanoformate. The reaction proceeded smoothly with a mild reaction condition to afford the cyanohydrin ethyl carbonates in
high yields (up to 96%) and good enantioselectivities (up to 85% enantiomeric excess). Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: Schiff base; asymmetric catalysis; titanium; cyanoformylation; ethyl cyanoformate
the catalytic performance of these Schiff base ligands in the
asymmetric addition of ethyl cyanoformate to aldehydes.
Optically active cyanohydrins serve as highly versatile synthetic
Introduction
building blocks in biologically active products.[1] They are stable
in the presence of moisture and air, and can therefore be widely
Results and Discussion
used in the synthesis of a-amino alcohols and b-substituted un-
saturated nitriles.[2] In the last two decades, HCN, K(Na)CN and
The Schiff base ligands 1a–g were synthesized according to our pre-
vious reports[17,18] and 1 h was synthesized following Jacobsen’s pro-
TMSCN (trimethylsilyl cyanide) have been used as the cyanide
cedure[19] (Fig. 2). 1a–d and 1f were prepared by condensation of the
source to react with carbonyl compounds to provide the optically
active cyanohydrins.[3,4] Recently, scientists have investigated
Cinchona alkaloid-derived 9-amino compounds with salicylaldehyde
some more promising cyanide candidates in this reaction. Ethyl
cyanoformate[5] (NCCO2Et) has been applied in the enantioselec-
tive cyanoformylation of aldehydes more frequently than others
because it is more stable and less toxic. The groups of Deng,[6]
Shibasaki,[7] North,[8] Saá,[9] Chinchilla,[10] Johnson[11] and
Moberg[12] have devoted much effort to this field. Although their
experiments have generally achieved high enantioselectivities
and yields, some of them still needed the multicomponent metal
complex,[13] harsh reaction conditions[14] and sometimes the
presence of alkaline additives.[10,12]
More recently, Feng reported the enantioselective cyanofor-
mylation of aldehydes activated by a series of combined catalyst
systems based on bifunctional catalysis methods[13,15] and the
self-assembly concept[16] (Fig. 1). Focusing on these catalyst sys-
tems, the combination of BINOL derivatives (1) with chiral amines
(2,3) or 2,20-biphenol derivatives (5) with Cinchona alkaloid (4) or
use of Schiff base (6) together with cinchonine (2) could improve
enantioselectivity and reactivity. Based on these reports, we hope
to synthesize a series of single molecules made up of the two inter-
esting parts (uncovered hydroxyl and Cinchona alkaloid) and ex-
plore whether they can activate the cyanoformylation of aldehydes
with ethyl cyanoformate. This study may also help us to understand
the possible transition state in this transformation more easily.
Very recently, we have developed a series of novel Schiff base
ligands from Cinchona alkaloids and salicylaldehyde deriva-
tives,[17,18] and the experimental results showed that they could
be successfully applied in the copper-catalyzed asymmetric
Henry reaction of various aldehydes. Herein, we wish to report
derivatives. 1b was methylated with dimethyl sulfate to afford 1e. 1 g
was obtained by the reaction of 1,2-benzenedialdehyde with (8S,9S)-
9-amino-(9-deoxy)-epiquinine.[17] The catalytic performance of
these ligands was evaluated.
Initially, the addition of NCCO2Et to benzaldehyde in CH2Cl2 at
ꢀ20ꢁC in the presence of chiral Schiff base 1a (5 mol%) was
investigated. Unfortunately, no reaction was observed after 48 h
(Table 1, entry 1), which indicated that 1a alone could not pro-
mote this reaction. Interestingly, in the presence of 1a (5 mol%)
and tetraisopropyl titanate [Ti(Oi-Pr)4] (5 mol%) (in situ), the reac-
tion proceeded smoothly and gave the product in 75% yield and
10% enantiomeric excess (ee) (Table 1, entry 2) under the same
conditions. Other metal precursors were also investigated. It
was found that when Ti(Oi-Pr)4 was replaced by TiCl4, enantios-
electivity reduced from 10% to 7% ee (Table 1, entry 3). When
Cu(OTf)2 was used in this reaction, only trace products could be
observed (Table 1, entry 4). Although the use of Cu(OAc)2.H2O
*
Correspondence to: Wei He, Department of Chemistry, School of Pharmacy,
Fourth Military Medical University, Xi’an 710032, People’s Republic of China.
E-mail: weihechem@fmmu.edu.cn; Yurong Li, Department of Radiation Medi-
cine, Fourth Military Medical University, Xi’an 710032, People’s Republic of China.
E-mail: 722lyr@fmmu.edu.cn
a Department of Chemistry, School of Pharmacy, Fourth Military Medical Univer-
sity, Xi’an 710032, People’s Republic of China
b Department of Radiation Medicine, Fourth Military Medical University, Xi’an
710032, People’s Republic of China
Appl. Organometal. Chem. 2013, 27, 209–213
Copyright © 2013 John Wiley & Sons, Ltd.

N. Ji et al.
10 mol% 1,2,3 or 5 mol% 4,5 or 5 mol% 2,6
10 mol% Ti(Oi-Pr)4 or 5 mol% Ti(Oi-Pr)4
solvents, -20oC ~ -45oC
OCOOEt
CN
RCHO
CNCOOEt
+
R
Br
N
H
N
HO
2
OH
OH
OH
Br
N
1
3
Ar
N
H
N
H
HO
4
N
HO
OH
OH
OH
MeO
t-Bu
OH
t-Bu
N
Ar
N
Ar= 2-naphthyl
6
5
2
Figure 1. Feng’s combined catalyst systems for cyanoformylation of aldehydes with ethyl cyanoformate.
OH
OH
N
N
N
N
N
9S
CH
HO HC
N
9R
N
9S
CH
N
9S
CH OH
8S
8S
8S
8R
MeO
MeO
MeO
N
N
N
N
1d
1b
t-Bu
1a
1c
t-Bu
OH
t-Bu
N
N
N
N
t-Bu
N
9S
CH OMe
N CH OH
9S
N
CH HC N
N
8S
8S
8S
8S
9S
9S
MeO
MeO
OMe
MeO
OH
N
1e
N
N
N
1g
1h
1f
Figure 2. Schiff base ligands 1a–h.
or VOSO4.XH2O respectively as the metal source together with 1a
could drive the reaction with good reactivity, only racemic pro-
ducts were obtained (Table 1, entries 5 and 6). Apparently, Ti
(Oi-Pr)4 was the best choice.
of this reaction was enhanced, while enantioselectivity declined
to a great extent (Table 1, entry 13).
It was found that the solvent frequently influenced reactivity
and enantioselectivity in various catalytic processes.[20] In order to
improve enantioselectivity, the catalytic activity of chiral Schiff base
1f with Ti(Oi-Pr)4 has been further evaluated for this reaction in vari-
ous solvents (Table 2). Lower enantioselectivity was obtained from
ether, acetonitrile and hexane (Table 2, entries 1–3). In the chlori-
nated solvents CHCl3 and CH2Cl2, moderate yields and medium
enantioselectivities were observed (Table 2, entries 4 and 5). No
corresponding product had been detected in toluene or THF (Table 2,
entries 6 and 7). Polar protic solvents isopropanol, n-propanol and
ethanol showed a similar level of activity enantioselectivity (Table 2,
entries 8–10). Surprisingly, performing the reaction in glycerol led
to a racemic product. Other conditions such as alkaline additives
and reaction time were also examined. However, the enantiomeric
excesses of the products were not satisfactory. Considering the bal-
ance between enantioselectivity and yield, ethanol was selected as
the optimized solvent for this reaction (Table 2, entry 10).
Subsequently, catalytic cyanoformylation using a series of
chiral Schiff bases 1a–h (Fig. 2) combined with Ti(Oi-Pr)4 was ex-
amined. As shown in Table 1, it was noteworthy that the skeleton
of the quinine has a more perceptible influence on enantioselec-
tivity than cinchonine (Table 1, entry 7 vs. 8), and the absolute
configuration of the product is determined by the C8-position
and C9-position configuration of Cinchona alkaloids. Moreover,
by comparison of the catalytic performance of the ligands 1a,
1b, 1d, 1e, 1f, all of which were derived from quinine, we can con-
clude that the hydroxyl group from salicylaldehyde was crucial
for chiral induction (Table 1, entries 2, 10 vs.7, 9, 11), which is con-
sistent with Feng’s observation. Chiral Schiff base 1f derived from
9-aminoquinine and 3,5-di-tert-butylsalicylaldehyde[18] turned
out to have the best architecture (Table 1, entry 11). C2 symmetric
chiral Schiff base 1 g gave the product with high yield but poor
enantioselectivity (Table 1, entry 12). When the skeleton of qui-
nine was replaced by chiral indene derivative (1 h),[19] the rate
The effect of several concentrations of benzaldehyde was also
tested under our catalytic system (Table 3), and experiments
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Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 209–213

Enantioselective cyanoformylation catalysed by ti/schiff base
Table 1. Screening of the Schiff base ligands and metals in the enan-
Table 3. Effects of concentration and temperature on the Ti(Oi-Pr)4 /1f
tioselective cyanoformylation of benzaldehyde
system catalyzed enantioselective cyanoformylation of benzaldehyde
Entrya Benzaldehyde conc.
Temperature Time Yield ee (%)
c
O
(mol Lꢀ1
)
(ꢁC)
(h)
(%)b
5 mol% catalyst
O
5 mol% metal
CH2Cl2, -20oC
O
OEt
CN
PhCHO
+
1
2
3
4
5
6
7
0.25
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ30
0
8
82
80
78
78
70
93
95
77
85
73
70
79
83
71
NC
OEt
*
Ph
0.125
0.08
8.5
8.5
8.5
3a
2a
4a
0.06
Entrya Catalyst
Metal
Time (h) Yield (%)b ee (%)c
0.125
0.125
0.125
12
6
1
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
—
48
12
12
48
12
10
12
12
12
12
12
12
7
trace
75
—
r.t.
4.5
2
Ti(Oi-Pr)4
TiCl4
10 (R)
7 (R)
—
aReactions were carried out on varied content of benzaldehyde in
ethanol with catalyst (5 mol%) and NCCO2Et (1.5 equiv.).
bIsolated yield.
cEnantiomeric excess, determined by HPLC on a Chiralcel OD-H column.
The absolute configuration was R, determined by comparison with
literature data.[15]
3
70
4
Cu(OTf)2
Trace
72
5
Cu(OAc)2 ꢂ H2O
VOSO4 ꢂ XH2O
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Rac.
6
76
Rac.
7
71
17 (R)
12 (S)
21 (R)
11 (R)
55 (R)
Rac.
8
73
9
70
10
11
12
13
75
revealed that the concentration of benzaldehyde had an
important effect on the reaction rate and enantioselectivity. When
the concentration of benzaldehyde was reduced from 0.25 M to
0.125 M, the enantioselectivity increased up to 85% ee (Table 3,
entry 1 vs. 2). Further lowering the concentration of benzaldehyde
was detrimental to ee value (Table 3, entry 2 vs. entries 3 and 4).
We also tested the effects of reaction temperature. Reducing
the temperature from ꢀ20ꢁC to ꢀ30ꢁC did not improve the
enantioselectivity and lowered the yield (Table 3, entry 5). On
the other hand, when the temperature was enhanced from
ꢀ20ꢁC to 0ꢁC, the yield of the reaction increased to 93%, while
the enantioselectivity was not significantly reduced (Table 3,
entry 6). When the reaction temperature was further increased to
room temperature from 0 ꢁC, the enantioselectivity decreased from
83% to 71% ee (Table 3, entry 7). To summarize, the optimized reac-
tion conditions for the model reaction were Ti(Oi-Pr)4 (5 mol%),
Schiff base 1f (5 mol%), 0.125 M aldehydes, at 0ꢁC in ethanol.
Under the optimized conditions, the generalities of this meth-
odology for a series of aldehydes were investigated, and the
results are summarized in Table 4. Almost all the tested
substrates, including aromatic, heteroaromatic and aliphatic
aldehydes, gave high yields (up to 96%) and moderate to good
enantioselectivities (up to 85% ee). It can be seen that the aro-
matic aldehydes with electron-donating group gave similar
results to benzaldehyde, except for heliotropin (Table 4, entries
2–11). Among them, 2-methoxybenzaldehyde (Table 4, entry 6)
gave the highest enantioselectivity (85% ee). On the other hand,
the aromatic aldehydes with electron-withdrawing group gave
lower ee value, even when adjusting the temperature to ꢀ50ꢁC
(Table 4, entries 10 and 11). The substrate scope was also
expanded to heterocyclic aldehydes and aliphatic aldehydes
(Table 4, entries 12–15). Furfural 2 l gave the product in highest
yield with 73% ee under ꢀ20ꢁC (Table 4, entry 12). Under the
same temperature, pyridylaldehyde 2 m gave the product
in 93% yield with 61% ee (Table 4, entry 13). The aliphatic
3-phenylpropionaldehyde 2n resulted also in a moderate
enantioselectivity (Table 4, entry 14). When amylcinnamaldehyde
2o was subjected to this reaction, 1,2-addition product was afford
in 90% yield and 71% ee (Table 4, entry 15).
70
1 g
1 h
83
81
5 (R)
aAll reaction were performed with benzaldehyde (0.25 mmol) and
NCCO2Et (0.375 mmol) in CH2Cl2 (1 ml) at ꢀ20ꢁC.
bIsolated yield.
cEnantiomeric excess, determined by HPLC on a Chiralcel OD-H column.
The absolute configurations were determined by comparison with
the literature data.[15]
Table 2. Screening the solvents in the enantioselective cyanoformy-
lation of benzaldehyde
O
O
O
OEt
CN
5 mol% 1f, -20oC
PhCHO
+
NC
OEt
*
Ph
5 mol% Ti(Oi-Pr)4
2a
3a
4a
Entrya
Solvent
Time (h)
Yield (%)b
Ee (%)c
1
Et2O
12
12
12
12
12
48
48
8
75
80
17
9
2
CH3CN
Hexane
CHCl3
3
73
25
35
55
—
—
71
73
77
Rac.
4
75
5
CH2Cl2
toluene
THF
70
6
Trace
Trace
78
7
8
i-PrOH
n-PrOH
ethanol
9
8
77
10
11
8
82
glycerol
8
90
aAll reactions were performed with benzaldehyde (0.25 mol) and
NCCO2Et (0.375 mmol) in solvent (1 ml) with 1f (5 mol%) and Ti
(Oi-Pr)4 (5 mol%) at ꢀ20ꢁC for 8–48 h.
bIsolated yield.
cDetermined by HPLC on a Chiralcel OD-H column. The absolute
configuration was R was determined by comparison with literature
data.[15]
Based on previous mechanism studies[5,7,13] of the cyanofor-
mylation of aldehydes with NCCO2Et and the experiments above,
we proposed a potential transition state to reveal the possible
Appl. Organometal. Chem. 2013, 27, 209–213
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N. Ji et al.
Table 4. Ti(Oi-Pr)4 /1f system-catalyzed enantioselective cyanofor-
mylation of aldehydes
1f and Ti(Oi-Pr)4, the reaction proceeded smoothly under mild con-
ditions to provide products with high yields and good enantios-
electivities (up to 96% yield and up to 85% ee). Further application
and mechanism studies are ongoing in our laboratory.
O
5 mol% 1f
O
O
*
OEt
CN
5 mol% Ti(Oi-Pr)4
RCHO
+
NC
OEt
R
ethanol, 0oC
Experimental
2a-o
3a
4a-o
General Remarks
Entrya
Substrate
Time (h) Yield (%)b ee (%)c
All reactions were run under an atmosphere of nitrogen using
oven-dried glassware. Solvents were prepared before use by
standard procedures. 1H and 13C NMR spectra were recorded
on Mercury 400 MHz or JEOL JNM-LA 100 MHz spectrometers.
Chemical shifts are expressed in parts per million downfield from
tetramethylsilane as internal standard, and coupling constants
are reported in hertz. Mass spectrometry was performed on a
Waters Q Tof Premier Micromass (ESI) spectrometer. Routine mon-
itoring of reactions was performed by thin-layer chromatography,
and visualization was done by fluorescence quenching at
254 nm or exposure to iodine vapor. Flash chromatography
was carried out on silica gel (Acme, 60–120 mesh). Melting
points were determined using YG252A apparatus and were
uncorrected. Optical rotations were measured on a PerkinElmer
343 polarimeter in the solvent indicated. IR spectra were
recorded as KBr disks on an FT-IR-8400S (CE). High-performance
liquid chromatography (HPLC) was performed using an Agilent
1260 interfaced to a HP71 series computer workstation with
Daicel Chiralcel OD-H column.
1
benzaldehyde (2a)
6
6
93
91
92
94
93
90
91
92
94
95
95
96
93
91
90
83
77
75
71
73
85
75
71
65
71
63
73
61
67
71
2
3-methylbenzaldehyde (2b)
4-methylbenzaldehyde (2c)
3-methoxybenzaldehyde (2d)
4-methoxybenzaldehyde (2e)
2-methoxybenzaldehyde (2f)
4-tert-butylbenzaldehyde (2 g)
4-isobutylbenzaldehyde (2 h)
heliotropin (2i)
3
6
4
6
5
6
6
6
7
6
8
6
9
10
12
12
10
10
6
10d
11d
12e
13e
14
15e
4-fluorobenzaldehyde (2j)
4-chlorobenzaldehyde (2 k)
furfural (2 l)
pyridylaldehyde (2 m)
3-Phenylpropionaldehyde (2n)
amylcinnamaldehyde (2o)
10
aAll reactions were performed with aldehydes (0.25 mmol) and
NCCO2Et (0.375 mmol) in ethanol (2 ml) at 0ꢁC, unless otherwise
indicated.
bIsolated yield.
Preparation of the Ligands (Fig. 2)
cDetermined by HPLC on a Chiralcel OD-H or Chiralcel AD-H column.
dReaction temperature ꢀ50ꢁC.
The ligands 1a–1h (Fig. 2) were synthesized according to previ-
ous reports[17–19] and the structures of these compounds were
confirmed by 1H NMR (see supporting information).
eReaction temperature ꢀ20ꢁC.
t-Bu
H
General Procedure for the Asymmetric Addition of Ethyl
Cyanoformate to Aldehydes
Ph
OiPr
O
t-Bu
O
O
CN
Ti
H
Ti(Oi-Pr)4 (1.0 M in toluene, 0.0125 mmol, 12.5 ml), Schiff base li-
gand 1f (0.0125 mmol, 6.75 mg) were dissolved in ethanol (2 ml)
at room temperature. The mixture was stirred at room tempera-
ture for 0.5 h. Then, the corresponding aldehyde (0.25 mmol)
was added, and NCCO2Et (1.5 equiv.) was added after 10 min at
0ꢁC. Stirring was continued for the time indicated in Table 4,
and the residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate, 15:1) to provide the
corresponding cyanohydrin carbonates. These adducts (4a–o)
were compared with those published in the literature by using
1H and 13C NMR spectra. The ee were determined by HPLC anal-
ysis on a Chiralcel OD-H or AD-H column (see supporting infor-
mation), and the absolute configurations were determined by
comparison with the literature data.[12–15]
N
EtO
N
MeO
N
Figure 3. Proposed transition state for this reaction.
mechanism of this asymmetric catalytic reaction. As shown in
Fig. 3, we considered that the hydroxyl group of salicylaldehyde
and nitrogen from the Schiff base double bond coordinated with
Ti(Oi-Pr)4 might act as a Lewis acid to activate the carbonyl group,
and the tertiary nitrogen atom of Cinchona alkaloid might act as
a base to activate the NCCO2Et. In this proposed working model,
the activated cyanide would attack the aldehydes through the
less hindered Re face, and then the corresponding product would
be afforded. Nevertheless, the detailed catalytic mechanism still
needs further investigation.
2-Ethoxycarbonyl (R)-2-hydroxy-2-phenyl-acetonitrile (4a),
93% yield, 83% ee. HPLC analysis (Chiralpak OD-H column,
hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 15.3 (major)
and 19.0 min (minor).
2-Ethoxycarbonyl (R)-2-hydroxy-2-(3-methylphenyl)-acetoni-
trile (4b), 91% yield, 77% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 7.2
(major) and 8.4 min (minor).
Conclusion
In summary, a new enantioselective catalytic cyanoformylation of
aldehydes with NCCO2Et through an additive-free process was de-
veloped. By using the catalyst in situ prepared by chiral Schiff base
2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-methylphenyl)-acetoni-
trile (4c), 92% yield, 75% ee. HPLC analysis (Chiralpak OD-H
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Enantioselective cyanoformylation catalysed by ti/schiff base
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 11.9
Acknowledgments
(major) and 13.8 min (minor).
The financial support of the National Natural Science Foundation
of China (21022228, 20702063) and Young Scholar Foundation of
the Fourth Military Medical University is gratefully acknowledged.
2-Ethoxycarbonyl (R)-2-hydroxy-2-(3-methoxylphenyl)-ace-
tonitrile (4d), 94% yield, 71% ee. HPLC analysis (Chiralpak
OD-H column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm).
tR = 16.5 (major) and 24.5 min (minor).
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2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-methoxylphenyl)-ace-
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column, hexane:i-PrOH= 99:1, 1 mlminꢀ1, 254 nm). tR = 18.9
(major) and 25.8 min (minor).
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Synth. Catal. 2006, 348, 538; e) Y. C. Qin, L. Liu, L. Pu, Org. Lett.
2005, 7, 2381.
2-Ethoxycarbonyl (R)-2-hydroxy-2-(2-methoxylphenyl)-aceto-
nitrile (4f), 90% yield, 85% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 6.8
(major) and 9.7 min (minor).
2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-tert-butylphenyl)-aceto-
nitrile (4g), 91% yield, 75% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH= 99:1, 1 mlminꢀ1, 254 nm). tR = 10.9
(major) and 12.8 min (minor).
2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-isobutylphenyl)-acetoni-
trile (4 h), 92% yield, 71% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 8.5
(major) and 9.7 min (minor).
2-Ethoxycarbonyl (R)-2-hydroxy-2-(benzo[d][1,3]dioxole-5-yl)-
acetonitrile (4i), colorless oil; 94% yield, 65% ee. Physical
and spectroscopic data consistent with those previously
reported. HPLC analysis (Chiralpak OD-H column, hexane:i-
PrOH = 99:1, 1 ml minꢀ1
22.3 min (minor).
, 254 nm). tR = 20.5 (major) and
2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-fluorophenyl)-acetoni-
trile (4j), 95% yield, 71% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 12.3
(major) and 15.5 min (minor).
[5] a) N. Yamagiwa, J. Tian, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc.
2005, 127, 3413; b) J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki,
Org. Lett. 2003, 5, 3021.
[6] a) S. K. Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195; b) S. K. Tian,
L. Deng, Tetrahedron 2006, 62, 11320.
2-Ethoxycarbonyl (R)-2-hydroxy-2-(4-chlorophenyl)-acetoni-
trile (4 k), 95% yield, 63% ee. HPLC analysis (Chiralpak OD-H
column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm). tR = 16.9
(major) and 23.8 min (minor).
[7] J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Angew. Chem. Int.
Ed. 2002, 41, 3636.
[8] a) Y. N. Belokon, A. J. Blacker, L. A. Clutterbuck, M. North, Org. Lett.
2003, 5, 4505; b) Y. N. Belokon, A. J. Blacker, P. Carta, L. A.
Clutterbuck, M. North, Tetrahedron 2004, 60, 10433; c) Y. N. Belokon,
E. Ishibashi, H. Nomura, M. North, Chem. Commun. 2006, 1775.
[9] a) J. Casas, A. Baeza, J. M. Sansano, C. Nájera, J. M. Saá, Tetrahedron:
Asymmetry 2003, 14, 197; b) A. Baeza, J. Casas, C. Nájera, J. M. Saá,
Eur. J. Org. Chem. 2006, 1949.
2-Ethoxycarbonyl (R)-2-hydroxy-2-furyl-acetonitrile (4 l), color-
less oil; 96% yield, 73% ee. Physical and spectroscopic data
consistent with those previously report. HPLC analysis (Chiral-
pak AD-H column, hexane:i-PrOH = 99:1, 1 ml minꢀ1, 254 nm).
tR = 15.6 (major) and 18.0 min (minor).
[10] R. Chinchilla, C. Nájera, F. J. Ortega, S. Tarí, Tetrahedron: Asymmetry
2009, 20, 2279.
[11] a) D. A. Nicewicz, C. M. Yates, J. S. Johnson, Angew. Chem. Int. Ed.
2004, 43, 2652; b) D. A. Nicewicz, C. M. Yates, J. S. Johnson, J. Org.
Chem. 2004, 69, 6548.
2-Ethoxycarbonyl (R)-2-hydroxy-2-pyridyl-acetonitrile (4 m),
yellow oil; 93% yield, 61% ee. Physical and spectroscopic data
consistent with those previously reported. HPLC analysis
[12] S. Lundgren, E. Wingstrand, M. Penhoat, C. Moberg, J. Am. Chem. Soc.
(Chiralpak AD-H column, hexane:i-PrOH = 99:1, 1 ml minꢀ1
254 nm). tR = 15.5 (major) and 18.2 min (minor).
,
2005, 127, 11592.
[13] J. Wang, W. T. Wang, W. Li, X. L. Hu, K. Shen, C. Tan, X. M. Feng, Chem.
Eur. J. 2009, 15, 11642.
[14] D. Peng, H. Zhou, X. H. Liu, L. W. Wang, S. K. Chen, X. M. Feng, Synlett
2-Ethoxycarbonyl (R)-2-hydroxy-4-phenyl-butanenitrile (4n),
colorless oil; 91% yield, 67% ee. Physical and spectroscopic
data consistent with those previously report. HPLC analysis
2007, 2448.
[15] S. H. Gou, X. H. Chen, Y. Xiong, X. M. Feng, J. Org. Chem. 2006, 71,
5732.
[16] W. T. Wang, S. H. Gou, X. H. Liu, X. M. Feng, Synlett 2007, 2875.
[17] Y. Wei, L. Yao, B. L. Zhang, W. He, S. Y. Zhang, Tetrahedron 2011,
67, 8552.
[18] L. Yao, Y. Wei, P. Wang, W. He, S. Y. Zhang, Tetrahedron 2012, 68, 9119.
[19] R. T. Ruck, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 2882.
[20] a) S. H. Gou, Z. B. Ye, G. Gou, M. M. Feng, J. Chang, Appl. Organomet.
Chem. 2011, 25, 110; b) S. Agrawal, R. I. Kureshy, S. H. R. Abdi, K. J.
Prathap, R. V. Jasra, N. H. Khan, Eur. J. Org. Chem. 2008, 4511.
(Chiralpak OD-H column, hexane:i-PrOH = 99:1, 1 ml minꢀ1
254 nm). tR = 28.6 (major) and 29.4 min (minor).
,
2-Ethoxycarbonyl (R)-2-hydroxy-3-amyl-4-phenyl-but-3-eno-
nitrile (4o), yellow oil; 90% yield, 71% ee. Physical and
spectroscopic data consistent with those previously
reported. HPLC analysis (Chiralpak OD-H column, hexane:i-PrOH =
99:1, 1 ml minꢀ1, 254nm). tR = 16.7 (major) and 17.7 min (minor).
Appl. Organometal. Chem. 2013, 27, 209–213
Copyright © 2013 John Wiley & Sons, Ltd.
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